3BL7

Synthetic Gene Encoded DcpS bound to inhibitor DG156844

3BL7 の概要

• エントリーDOI: 10.2210/pdb3bl7/pdb
• 関連するPDBエントリー: 1ST0 1ST4 3BL9 3BLA
• 分子名称: Scavenger mRNA-decapping enzyme DcpS, 5-{[1-(2-fluorobenzyl)piperidin-4-yl]methoxy}quinazoline-2,4-diamine (3 entities in total)
• 機能のキーワード: mrna decapping enzyme, dcps, ligand complex, cytoplasm, hydrolase, nonsense-mediated mrna decay, nucleus, polymorphism, structural genomics, psi-2, protein structure initiative, accelerated technologies center for gene to 3d structure, atcg3d
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q96C86
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 70164.67

構造登録者

Staker, B.L.,Christensen, J.,Stewart, L.,Accelerated Technologies Center for Gene to 3D Structure (ATCG3D) (登録日: 2007-12-10, 公開日: 2008-10-21, 最終更新日: 2023-08-30)

主引用文献

Singh, J.,Salcius, M.,Liu, S.W.,Staker, B.L.,Mishra, R.,Thurmond, J.,Michaud, G.,Mattoon, D.R.,Printen, J.,Christensen, J.,Bjornsson, J.M.,Pollok, B.A.,Kiledjian, M.,Stewart, L.,Jarecki, J.,Gurney, M.E.
DcpS as a therapeutic target for spinal muscular atrophy.
Acs Chem.Biol., 3:711-722, 2008

PubMed Abstract: Spinal muscular atrophy (SMA) is caused by deletion or mutation of both copies of the SMN1 gene, which produces an essential protein known as SMN. The severity of SMA is modified by variable copy number of a second gene,SMN2, which produces an mRNA that is incorrectly spliced with deletion of the last exon. We described previously the discovery of potent C5-substituted quinazolines that increase SMN2 gene expression by 2-fold. Discovery of potent SMN2 promoter inducers relied on a cellular assay without knowledge of the molecular target. Using protein microarray scanning with a radiolabeled C5-substituted quinazoline probe, we identified the scavenger decapping enzyme, DcpS, as a potential binder. We show that the C5-substituted quinazolines potently inhibit DcpS decapping activity and that the potency of inhibition correlates with potency forSMN2 promoter induction. Binding of C5-substituted quinazolines to DcpS holds the enzyme in an open, catalytically incompetent conformation. DcpS is a nuclear shuttling protein that binds and hydrolyzes the m(7)GpppN mRNA cap structure and a modulator of RNA metabolism. Therefore DcpS represents a novel therapeutic target for modulating gene expression by a small molecule.

PubMed: 18839960
DOI: 10.1021/cb800120t

実験手法

X-RAY DIFFRACTION (2.31 Å)